Tuberculosis (TB) is caused by Mycobacterium tuberculosis and remains as a leading cause of mortality worldwide. The treatment is complicated by a long-term administration of few antitubercular agents such as Rifampicin, Isoniazid, Ethambutol and Pyrazinamide in high dosage which intensifies drug side effects, and often results in the development of multidrug resistant strains and thus poor compliance from TB patients. In addition, the disease often attacks immunoaltered individuals. TB together with mycoses is the most common complication and the cause of death in AIDS patients. The failure of anti tubercular therapy is also related to migration of inhabitants from the areas with a higher incidence of TB to the regions with a favorable epidemiologic situation. Thus the current TB treatment is found to be not satisfactorily effective in the eradication of latent TB infection.
Triazoles are known for their antifungal, antiviral and plant growth regulatory activities but their antimycobacterial potential has gained importance only in recent years. Fluconazole and tebuconazole are known for their antimycobacterial activity but have non-specificity and higher MIC values. Moreover, they are not effective against dormant tubercle bacilli.
Further, azole antifungal derivatives such as fluconazole, hexacoazole which are N1 substituted 1,2,4-triazole compounds were found to be ergosterol biosynthesis inhibitors.
There is ample non-patented literature available on development of tubercular drugs as quoted below: References may be made to article “Arch Pharm Res Vol 27, No 5, 502-506, 2004” by Alireza Foroumadi, et al, which discloses two series of 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-propyl, allyl and propargyl)thio-1,3,4-thiadiazoles and 2-(5-nitro-2-furyl)- and 2-(1-methyl-5-nitro-1H-imidazol-2-yl)-5-(nitrobenzyl)thio-1,3,4-thiadiazole derivatives which were evaluated against Mycobacterium tuberculosis. The compounds 2-(3-Methyl-5-nitro-1H-imidazol-2-yl)-5-(n-propyl)thio-1,3,4-thiadiazole, 2-(5-nitro-2-furyl)-5-(2-propynyl)thio-1,3,4-thiadiazole, 2-(5-nitro-2-furyl)-5-(2-nitrobenzyl)thio-1,3,4-thiadiazole, 2-(5-nitro-2-furyl)-5-(3-nitrobenzyl)thio-1,3,4-thiadiazole, 2-(5-nitro-2-furyl)-5-(4-nitro benzyl)thio-1,3,4-thiadiazole displayed significant inhibition effects (90%) in the primary screening (MIC>>6.25 μg/mL) against M. tuberculosis H37Rv in the BACTEC 12B medium, using the BACTEC 460 radiometric system.
References may be made to Journal “Enzyme Inhibition and Medicinal Chemistry, Volume 22, issue 4 Aug. 2007, pages 511-516” by Gulhan Turan-et al where it discloses another study, wherein a series of 4-arylidenamino-4H-1,2,4-triazole-3-thiol derivatives were synthesized by reaction of 4-amino-4H-1,2,4-triazoles-3-thiol with the respective aldehydes and were evaluated for anti tuberculosis activity against Mycobacterium tuberculosis H37Rv (ATCC 27294), using the BACTEC 460 radiometric system and BACTEC 12B medium. Compounds showed an activity at 6.25 μg/mL with 87 percentage inhibition.
In another article, a series of N-(4-{(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl)-1,3-thiazol-2-yl}-2-substituted amide derivatives were synthesized and evaluated for their preliminary in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by the MABA assay method.
Compounds such as N-(5-{[((1E)-1-aza-2-phenylvinyl)carbamoyl)methylthio}-3-{[2-(acetylamino)(1,3-thiazol-4-yl))methyl}(1,2,4-triazol-4-yl))-acetamide, N-(4-[(5-{(((1E)-1-aza-2-phenylvinyl)carbamoyl]methylthio)-4-acetylamino(1,2,4-trizol-3-yl))methyl](1,3-thiazol-2-yl)}-2-chloroacetamide and N-(5-{[((1E)-1-aza-2-phenylvinyl)carbamoyl]methylthio]-3-([2-(phenylamino)(1,3-thiazol-4-yl])methyl}(1,2,4-triazol-4-yl))-acetamide exhibited more than 94% inhibition at 12.5 μg/mL. [Mahendra Shiradkar, et al, General Papers, ARKIVOC 2006 (xiv) 141-154].
A series of 5-amino-4-(5-arylpyrazol-3-yl)-1-(3/4-nitrophenyl)-1,2,3-triazoles that have been synthesized by the base-catalysed condensation of 3/4-nitrophenyl azides with 5-aryl-3-cyanomethylpyrazoles is disclosed as potential antiinvasive and antimycobacterial agents by Ajay Kumar, et al in Indian Journal of Chemistry Sect. B Organic Chemistry including Medicinal Chemistry VOL. 42B NUMBER 8 Aug. 2003 Paper 1950.
References may be made to article “Structural elucidation of propargylated products of 3-substituted-1,2,4-triazole-5-thiols by NMR techniques in Magnetic Resonance Chemistry, 2005 December; 46(12):1168-74” by Chaudhary P M, Chavan S R, Kavitha M having DOI 10.1002/mrc.2307, which discloses synthesis and characterization of mono S-propargyl and S,N-dipropargyl regioisomers, arising from N1/N2 substitution to study their biological activity.
References may be made to Journal “European Journal of Medicinal Chemistry Volume 43, Issue2, February 2008, Pages 381-392” by Ilkay Küçkgüzel, et al, which discloses heterocyclic derivatives of 5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-ylthiones and N-alkyl/aryl-N′-{4-[(4-alkyl/aryl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methoxy]phenyl}thioureas.

The above compound showed 79% Inhibition against M. tuberculosis H37Rv where R1 is CH2CH═CH2, R2 is C6H5, X is —O—CH2—.
References may be made to Journal “Indian Journal of Chemistry Sect. B Organic Chemistry including Medicinal Chemistry VOL. 42B No. 8 August 2003 Paper 2010” by B Shivarama Holla, Veerendra, M K Shivananda & N Sucheta Kumari, which discloses synthesis and antibacterial activity of Schiff bases and bis-triazolothiadiazoles derived from bis-1,2,4-triazole.
References may be made to Article “UDC 547.791′796.07” by L I. Vereshchagin, et al, which discloses a number of corresponding 1- and 2-propargylazoles which were obtained by propargylation of 5-substituted tetrazoles and 1,2,3-triazoles with various degrees of substitution. These polyazole structures with a system of two to five uncondensed azole rings were synthesized by the reaction of 1- and 2-propargyl azoles with organic azides, diazides, and azoles, as well as by oxidative dimerization. The uncondensed polynitrogenous heterocyclic compounds were shown to exhibit pesticidal activity.
There still remains a need to develop antitubercular compounds to overcome the limitations encountered in the tuberculosis drug discovery programme as evident from the prior art.
Thus the present inventors felt a need to develop novel azole derivatives which are capable of inhibiting the growth of dormant tuberculi bacilli such as Mycobacterium bovis BCG and M. tuberculosis completely.